Stephania japonica Miers and Sinomenium acutum Rehd et Wile(Menispermaceae), which are found in southern parts and Cheju island in the Republic of Korea, have been used for long time as an analgesic and anti-inflammatory agent. On the other hand, S. tetrandra S. Moore(Menispermaceae), which is not found in the Republic of Korea, has been used traditionally as remedies for neuralgia and arthritis in, e.g., China. Especially, the alkaloid tetrandrine has been used as, e.g., an anti-inflammatory and anti-hypertensive agent. S. tetrandra S. Moore has been reported to have anti-phagocytic and anti-oxidizing effects (Seow, W. K., et al., Int. Archs. Allergy Appl. Immun., 85, 404(1988)), and to exhibit effectiveness in clinical and experimental silicosis models (Li, Q., et al., Chinese J. Tuberc. Resp. Dis., 4, 321(1981); Xu, X., et al., Ecotoxicol. Environ. Safety, 7, 306(1983); and Liu, B., et al., Ecotoxicol. Environ. Safety, 7, 323(1983)), and is known to have the ability to inhibit the production of interleukin-1 and tumor necrosis factor-a which are secreted by human monocytes (Seow, W. K., et al., Clin. Exp. Immunol., 75, 47(1989); and Ferrante, A., et al., Clin. Exp. Immunol., 80, 232(1990)). Tetrandrine and its derivatives are reported to promote the function of brain(Tsumura & CO, WPI Acc. No.: 92-231935 (1992)) and have been developed as an antimalarial drug and also a stimulant for hair growth (Sunstar KK, WPI Acc. No.: 89-117236(1989)).
As is well known, IL-6 is a regulatory factor which participates in the growth, differentiation and activation of cells. It is produced and secreted by various organ cells, and plays an important role in defensive mechanisms of a human body (Hirano, T., et al., Immunol. Today, 11, 443(1990)).
IL-6, first discovered in a culture of monocytes, has been reported to induce the production of antibodies by B cells (Muraguchi, A., et al., J. Immunol., 127, 412(1981)). Since the successful cloning of the cDNA of IL-6 by Hirano, T., et al. (Nature, 324, 73(1986)), IL-6 has been reported to serve as a growth factor for B cell hybridome and plasmocytoma (Snick, V. J., et al., Proc. Natl. Acad. Sci. U.S.A., 83, 9679(1986)), and as a factor participating in hematopoiesis (Koike, K., et al., J. Exp. Med., 168, 879(1988)). Further, IL-6 has been reported to have the functions of: stimulating the activation and growth of T cells (Lotz, M., et al., J. Exp. Med., 167, 1253(1988)); inducing the acute phase response of liver cells (Geiger, T., et al., Eur. J. Immunol., 18, 717(1988)); regulating cell differentiation in nerve system (Satoh, T., Mol. Cell. Biol., 8, 3546(1988)); stimulating the growth of keratinocytes; regulating a bone metabolism; stimulating the growth of kidney mesangial cells; inhibiting the growth of melanoma and breast cancer cells, etc.
As has been reported, various diseases may result from an improper regulation of IL-6 production. Examples of the diseases reported are rheumatoid arthritis (Hirano, T., et al., Eur. J. Immnol., 18, 1797(1988)), hepatocirrhosis (Deviere, J., et al., Clin. Exp. Immunol., 77, 221(1989)), psoriasis (Grossman, R. M., et al., Proc. Natl. Acad. Sci. U.S.A., 86, 6367(1989)), multiple myeloma (Bataille, R., et al., J. Clin. Invest., 84, 2008(1989)), cardiac myxoma, AIDS (Miles, S. A., et al., Proc. Natl. Acad. Sci. U.S.A., 87, 4068(1990)), and other autoimmune diseases. These observations have buttressed the importance of regulating the IL-6 production for the maintenance of the homeostasis of immune system in a human body and for the treatment and prophylaxis of diseases.
Accordingly, there have been proposed numerous approaches to regulate the production of interleukins. For instance, proliferation of myelocytes in a patient suffering from myeloma which is caused by an excessive secretion of IL-6 has been suppressed by employing antibodies against IL-6 or IL-6 receptor (Suzuki, H., Eur. J. Immunol., 22, 1989(1992)). However, no substance or method has been reported to inhibit specifically the production of IL-6 and, therefore, there has still existed a need for the discovery of specific inhibitors against the production of IL-6.